Percutaneously absorbable patch

ABSTRACT

A percutaneously absorbable preparation-containing patch, wherein the preparation comprises: (1) a base comprising as essential ingredients a (A-B) n-A based elastomer wherein A is substantially a monovinyl-substituted aromatic compound polymer block, B is substantially a conjugated diolefin copolymer block, and n is an integer of 3-7, crotamiton, and a softening agent; and (2) at least two hormones, especially estrogen and luteal hormones, as active ingredients.

This application is a 35USC371 of PCT/JP95/02336 filed Nov. 15, 1995.

TECHNICAL FIELD

This invention relates to a percutaneously absorbablepreparation-containing patch suitable for persistently releasingestrogen and luteal hormone as medicinal ingredients from thepreparation.

BACKGROUND ART

Estradiol contained in estrogen is secreted from the ovary of a womanduring her reproducible period of time. Thus, women who are at themenopause or thereabouts become lacking in estradiol whereupon theysuffer from their menopausal disorder, irregular menstruation or thelike. Remedies for these symptoms are now taken by the use of orallyadministrable preparations, but these preparations are rapidlymetabolized by digestive canals such as stomachs and intestines and alsoby livers to be made inactive. Thus, in order to obtain sufficientmedicinal efficacy, a large dose of estradiol must be administered. Theuse of such a high dose is very likely to cause adverse side effects andthe like.

Accordingly, the use of estradiol in combination with luteal hormone,which, through percutaneous administration, can reduce the metabolism ofestradiol and permits the estradiol to reach blood and, at the sametime, inhibits the side effects of the estradiol per se, has beenstudied in the art.

For example, Japanese Pat. Appln. Laid-Open Gazette No. 342532/92discloses a percutaneously absorbable preparation which comprisesestradiol and luteal hormones as active ingredients and a tackifiercomposed mainly of an acrylic tackifier consisting of 2-ethylhexylacrylate and N-vinyl-2-pyrrolidone. The acrylic tackifier, however, haspoor capability of releasing drugs and has strong irritation to theskin, thereby rendering said preparation unsuitable for continuousadministration for a long period of time. Japanese Patent Gazette No.51623/94 discloses a method wherein estradiol and norethisterone acetateas active ingredients are dissolved in a gel comprising hydroxypropylcellulose and ethanol, this is then formed to a reservoir type, and therelease of the active ingredients is regulated with the aid of apermeant regulating membrane. Ethanol, however, has strong irritation tothe skin and causes side effects such as rubefaction atpreparation-applied sites very frequently.

The percutaneously absorbable patches containing a preparation undervarious studies as mentioned above are low in biological utility sincethe active ingredients contained therein can be used only to a limitedextent. In addition, the tackifier per se or the addition of absorptionaccelerators such as ethanol will raise a problem of skin irritationsince the preparation is attempted to be percutaneously administered.

SUMMARY OF THE INVENTION

In view of the above disadvantages, the inventors of this invention havemade intensive studies with a view to providing percutaneouslyabsorbable patch containing a preparation, which has

1) a simple structure,

2) improved biological utility, and

3) reduced skin irritation thus completing this invention.

Thus, the percutaneously absorbable preparation-containing patch of thisinvention comprises: (1) a base comprising as essential ingredients a(A-B) n-A based elastomer (elastic polymer) (wherein A is substantiallya monovinyl-substituted aromatic compound polymer block, B issubstantially a conjugated diolefin copolymer block and n is an integerof 3-7), crotamiton and a softening agent; and (2) at least two hormonesas active ingredients.

According to this invention, at least two hormones are contained as theactive ingredients. Estrogen and luteal hormone are usually used as thetwo active ingredients.

Examples of the estrogen are estradiol, estrone, estriol, equilin,equilenin and derivatives thereof. Among them, estradiol is usually usedin the percutaneously absorbable preparation contained in the patchaccording to this invention.

The luteal hormone is suitably selected from the group consisting ofprogesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate,dydrogesterone, chlormadinone acetate, ethisterone, dimethisterone,norethisterone, norethisterone acetate, norethisterone enanthate,ethynodial acetate, megestrol acetate and allylestrenol.

The content of the estrogen exemplified by the estradiol is 0.01 to 10%by weight, preferably 0.05 to 5% by weight, more preferably 0.1 to 1% byweight, based on the total amount of the pharmaceutical preparation.Although the content of the luteal hormone varies depending upon thekind thereof, it is usually 0.01 to 10% by weight, preferably 0.05 to 5%by weight, more preferably 0.1 to 1% by weight, based on the totalamount of the pharmaceutical preparation. The content of the lutealhormone is preferably 1 to 5 times (weight ratio) that of estrogenexemplified by estradiol.

In this invention, the (A-B) n-A based elastomers usable as the base arethose which are commercially easily available and include astyrene-butadiene-styrene block copolymer (trade name: Califlex TR-1101produced by Shell Chemical Corp.), a styrene-isoprene-styrene blockcopolymer (trade name: Califlex TR-1107 and Califlex TR-1111 produced byShell Chemical Corp.), a styrene-isoprene-styrene block copolymer (tradename: JSR 5000 and JSR 5100 produced by Nippon Synthetic Rubber Co.) anda styrene-isoprene-styrene block copolymer (trade name: Quintack 3421produced by Nippon Zeon Co.) with the styrene-isoprene-styrene blockcopolymer being particularly preferred. The use of the (A-B) n-A typeelastomers as the base for the preparations will greatly enhance thereleasability of the estrogen exemplified by estradiol and the lutealhormone as well as the biological utilizability thereof.

Crotamiton used in this invention markedly improves the preparations insolubility of both the estrogen exemplified by estradiol and the lutealhormone contained in the preparations, in releasability of these activeingredients from the preparations, and in percutaneous absorption ofthese active ingredients and the like. Further, crotamiton has neverbeen incorporated as a solubilizer and absorption accelerator for theestrogen (exemplified by estradiol) and the luteal hormone into the(A-B) n-A based elastomer supported preparation before theaccomplishment of this invention and there is found no literature whichsuggests such incorporation of crotamiton as mentioned above.

Examples of softening agents used in this invention include liquidparaffin, polybutene, castor oil, cotton seed oil, palm oil, coconutoil, and process oil.

The use of the base containing as the essential components the (A-B) n-Atype elastomer, the crotamiton, and the softening agent will enhance thebiological utilizability of said hormones and will reduce rubefactionand rash which are otherwise caused by medicinal irritation to the skin.

The preferable contents of the (A-B) n-A based elastic polymer, thecrotamiton, and the softening agent in the percutaneously absorbablepreparation contained in the patch according to this invention are asfollows.

The total content of the essential ingredients consisting of the (A-B)n-A based elastomer and the crotamiton, is preferably 20 to 99% byweight, more preferably 30 to 60% by weight based on the total amount ofthe preparation. For the content of each ingredient, the content of the(A-B) n-A based elastomer is preferably 5 to 50% by weight, morepreferably 10 to 20% by weight, based on the total amount of thepreparation, the content of the crotamiton is preferably 1-20% byweight, more preferably 3 to 10% by weight, based on the total amount ofthe preparation, and the content of the softening agent is preferably 10to 70% by weight, more preferably 20 to 65% by weight, based on thetotal amount of the preparation. The combination of the ingredientshaving the above respective contents is best for attaining the effect ofthis invention.

The percutaneously absorbable preparation contained in the patch of thisinvention may contain conventional additives in addition to the aboveessential ingredients. Specific examples of the conventional additivesare synthetic rubbers, such as polyisobutyrene; tackifiers, such assaturated alicyclic hydrocarbon resins (for example, Arcon P-100 (tradename)), rosin esters (for example, KE-311 (trade name), KE-100 (tradename), or Super Ester S-100 (trade name)), alicyclic hydrocarbons (forexample, Escorez 5300 (trade name)), terpene hydrogenated resins (forexample, Clearon P-105 (trade name)), and hydrogenated rosin esters (forexample, Foral 105 (trade name)); and super absorbent polymers, such asSumikagel SP-520 (trade name), Aquakeep 4SH (trade name), Arasorb 800F(trade name), Sunwet 1M-300MPS (trade name), and Sunwet 1M-1000MPS(trade name), and inorganic fillers, such as zinc calcium carbonate,titanium dioxide, and silica. They may be added in a suitable amount.

The content of the tackifier is 0 to 40% by weight based on the totalamount of the preparation and, when the maintenance of satisfactorytackiness is required, is 5 to 40% by weight based on the total amountof the preparation. Although the above content suffices for attainingthe purposes, it is more preferably 10 to 30% by weight. The content ofthe water-absorptive polymer is 0 to 15% by weight based on the totalamount of the preparation and, when optionally added to the preparation,is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.

The support for the preparation of this invention is preferably onehaving no influence on the release of the drug and, in addition,superior flexibility and is preferably selected from a film or wovenfabric of polyester, polypropylene, polyethylene or the like and analuminum foil, or a flexible composite material comprising a laminate ofthese plastic films or woven fabrics.

The dosage form of the percutaneously absorbable preparation containedin the patch of this invention is preferably a plaster, particularlypreferably an anhydrous plaster.

A general process for producing the percutaneously absorbablepreparation-containing patch of this invention will be describedhereunder. All ingredients of a base except for crotamiton are heatmelted and then incorporated with active ingredients and crotamiton toobtain a preparation which is then spread over a support, covered with aliner and then cut into a desired shape to producepreparation-containing patches. Alternatively, the preparation may beonce applied over a film which has been treated to be made releasable,after which the preparation-applied film was pressed against a suitablesupport to transfer the spread preparation thereto, and suitably cutthereby producing preparation-containing patches. Further, it is alsopossible to use a method which comprises dissolving all the ingredientsin an organic solvent such as hexane, toluene or ethyl acetate,spreading the solution on a support, removing the organic solvent toproduce a preparation, covering the preparation with a liner and thencutting the preparation-coated support into a predetermined shape toproduce preparation-coated patches, or a method which comprises oncespreading the above solution over a film which has been treated to bemade releasable, removing the organic solvent, transferring theresulting preparation to a suitable support by pressing it against thesupport thereby to produce preparation-attached patches.

The percutaneously absorbable preparation-attached patches of thisinvention thus prepared can enhance the release of the estrogenexemplified by estradiol and the luteal hormone as active ingredients,improve the biological utilizability of these active ingredients and, atthe same time, have the effect of markedly relieving the skin irritationin case of continuous administration and long-term administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows data on estradiol in a percutaneous permeation test 1 onhairless mice. In the same Fig., the abscissa represents thepreparation-applied time (hr), the ordinate the amount of thepercutaneous permeation (μg/cm²), ◯ data on estradiol of Example 2, □data on estradiol of Reference Example 1 and Δ data on estradiol ofReference Example 2.

FIG. 2 shows data on norethisterone acetate in a percutaneous permeationtest 1 on hairless mice. In the same Fig., the abscissa represents thepreparation-applied time (hr), the ordinate the amount of thepercutaneous permeation (μg/cm²), ◯ data on norethisterone acetate ofExample 2, □ data on norethisterone acetate of Reference Example 1 anddata on norethisterone acetate of Reference Example 2.

FIG. 3 shows data on estradiol in a percutaneous permeation test 2 onhairless mice. In the same Fig., the abscissa represents thepreparation-applied time (hr), the ordinate the amount of thepercutaneous permeation (μg/cm²), ◯ data on estradiol of Example 23, □data on estradiol of Example 17, Δ data on estradiol of Example 15 and ▪data on estradiol of Comparative Example 1.

FIG. 4 shows data on norethisterone acetate in a percutaneous permeationtest 2 on hairless mice. In the same Fig., the abscissa represents thepreparation-applied time (hr), the ordinate the amount of thepercutaneous permeation (μg/cm²), ◯ data on norethisterone acetate ofExample 23, □ data on norethisterone acetate of Example 17, Δ data onnorethisterone acetate of Example 15 and ▪ data on norethisteroneacetate of Comparative Example 1.

FIG. 5 shows data on estradiol in a test for measuring the activeingredients concentration in the blood of rabbits. In the same Fig., theabscissa represents the preparation applied time (hr), the ordinate theestradiol concentration in the blood (ng/ml), ◯ data on estradiol ofExample 23, □ data on estradiol of Example 17, Δ data on estradiol ofExample 15 and ▪ data on estradiol of Comparative Example 1.

FIG. 6 shows data on norethisterone acetate in a test for measuring theactive ingredients concentration in the blood of rabbits. In the sameFig., the abscissa represents the preparation-applied time (hr), theordinate the norethisterone acetate concentration in the blood (ng/ml),◯ data on norethisterone acetate of Example 23, □ data on norethisteroneacetate of Example 17, Δ date on norethisterone acetate of Example 15and ▪ data on norethisterone acetate of comparative Example 1.

PREFERRED EMBODIMENTS OF THE INVENTION

This invention will be described in more detail referring to thefollowing Examples, Test Examples and the like. In Examples, ComparativeExamples and Reference Examples, all the numerical values are in % byweight.

Example 1

    ______________________________________                                        Styrene-isoprene-styrene                                                                          37.00                                                     block copolymer (trade name:                                                  Califlex TR-1107)                                                             Liquid paraffin     61.78                                                     Butylhydroxytoluene 0.20                                                      Crotamiton          1.00                                                      Estradiol           0.01                                                      Norethisterone acetate                                                                            0.01                                                      ______________________________________                                    

Using the above ingredients, a preparation was prepared, spread on asupport and cut into a desired size, in accordance with the abovegeneral production process to produce a patch containing apercutaneously absorbable preparation of a estradiol/norethisteroneacetate mixture type.

Example 2

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1107)                                                Liquid paraffin        57.00                                                  Crotamiton             5.00                                                   Estradiol              0.50                                                   Norethisterone acetate 2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 3

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             28.00                                                  (Trade name: Califlex TR-1107)                                                Liquid paraffin        27.00                                                  Crotamiton             20.00                                                  Super absorbent polymer                                                                              5.00                                                   (Trade name: Sumikagel SP-520)                                                Estradiol              10.00                                                  Norethisterone acetate 10.00                                                  ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 4

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        56.00                                                  Crotamiton             5.00                                                   Super absorbent polymer                                                                              1.00                                                   (Trade name: Aquakeep 4SH)                                                    Estradiol              0.50                                                   Norethisterone         2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 5

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             20.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        53.00                                                  Crotamiton             3.00                                                   Super absorbent polymer                                                                              20.00                                                  (Trade name: Aquakeep 4SH)                                                    Estradiol              1.00                                                   Norethisterone         3.00                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 6

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1107)                                                Liquid paraffin        52.00                                                  Crotamiton             5.00                                                   Super absorbent polymer                                                                              5.00                                                   (Trade name: Arasorb 800F)                                                    Estradiol              0.50                                                   Norethisterone         2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 7

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        52.00                                                  Crotamiton             4.00                                                   Super absorbent polymer                                                                              5.00                                                   (Trade name: Arasorb S-100F)                                                  Estradiol              1.00                                                   Norethisterone         3.00                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 8

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        53.00                                                  Crotamiton             5.00                                                   Super absorbent polymer                                                                              5.00                                                   (Trade name: Sunwet IM-300MPS)                                                Estradiol              0.50                                                   Medroxyprogesterone acetate                                                                          1.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 9

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             35.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        53.00                                                  Crotamiton             5.00                                                   Super absorbent polymer                                                                              5.00                                                   (Trade name: Sunwet IM-1000MPS)                                               Estradiol              0.50                                                   Medroxyprogesterone acetate                                                                          1.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 10

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               40.00                                                (Trade name: Califlex TR-1111)                                                Polyisobutylene          5.00                                                 Liquid paraffin          37.70                                                Butylhydroxytoluene      0.30                                                 Crotamiton               5.00                                                 Tackifier (alicyclic saturated hydrocarbon resin)                                                      10.00                                                (Trade name: Arcon F-100)                                                     Estradiol                0.50                                                 Medroxyprogesterone acetate                                                                            1.50                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 11

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               5.00                                                 (Trade name: Califlex TR-1107)                                                Polyisobutylene          10.00                                                Liquid paraffin          40.00                                                Crotamiton               6.00                                                 Tackifier (alicyclic saturated hydrocarbon resin)                                                      35.00                                                (Trade name: Arcon P-100)                                                     Estradiol                1.00                                                 Medroxyprogesterone acetate                                                                            3.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 12

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               50.00                                                (Trade name: Califlex TR-1107)                                                Liquid paraffin          26.00                                                Butylhydroxytoluene      0.50                                                 Crotamiton               5.00                                                 Super absorbent polymer  2.00                                                 (Trade name: Arasorb S-100F)                                                  Tackifier (alicyclic saturated hydrocarbon resin)                                                      12.50                                                (Trade name: Arcon P-100)                                                     Estradiol                1.00                                                 Progesterone             3.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/progesteronemixture type.

Example 13

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             27.00                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        41.00                                                  Crotamiton             3.00                                                   Tackifier (rosin ester)                                                                              25.00                                                  (Trade name: KE-311)                                                          Estradiol              1.00                                                   Progesterone           3.00                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/progesteronemixture type.

Example 14

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               50.00                                                (Trade name: Califlex TR-1111)                                                Polyisobutylene          2.00                                                 Liquid paraffin          30.80                                                Butylhydroxytoluene      0.20                                                 Crotamiton               5.00                                                 Tackifier (hydrogenated alicyclic hydrocarbon)                                                         10.00                                                (Trade name: Escorez 5300)                                                    Estradiol                0.50                                                 Progesterone             1.50                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/progesteronemixture type.

Example 15

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               20.00                                                (Trade name: Califlex TR-1111)                                                Liquid paraffin          33.00                                                Crotamiton               5.00                                                 Tackifier (alicyclic saturated hydrocarbon resin)                                                      36.00                                                (Trade name: P-100)                                                           Estradiol                1.00                                                 Norethisterone acetate   5.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 16

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               29.50                                                (Trade name: Califlex TR-1111)                                                Liquid paraffin          30.00                                                Crotamiton               7.50                                                 Super absorbent polymer  10.00                                                (Trade name: Sunwet IM-1000MPS)                                               Tackifier (hydrogenated alicyclic hydrocarbon)                                                         20.00                                                (Trade name: Escorez 5300)                                                    Estradiol                0.50                                                 Norethisterone acetate   2.50                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 17

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               22.50                                                (Trade name: Califlex TR-1107)                                                Liquid paraffin          39.50                                                Crotamiton               10.00                                                Tackifier (alicyclic saturated hydrocarbon resin)                                                      25.00                                                (Trade name: P-100)                                                           Estradiol                0.50                                                 Norethisterone acetate   2.50                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 18

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             5.00                                                   (Trade name: Califlex TR-1111)                                                Liquid paraffin        60.00                                                  Crotamiton             3.00                                                   Tackifier (rosin ester)                                                                              30.00                                                  (Trade name: Super Ester S-100)                                               Estradiol              1.00                                                   Norethisterone         1.00                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 19

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               27.00                                                (Trade name: Califlex TR-1111)                                                Liquid paraffin          40.00                                                Crotamiton               5.00                                                 Tackifier (alicyclic saturated hydrocarbon resin)                                                      25.00                                                (Trade name: Arcon P-100)                                                     Estradiol                1.00                                                 Norethisterone           2.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteronemixture type.

Example 20

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               34.50                                                (Trade name: Califlex TR-1107)                                                Liquid paraffin          42.50                                                Crotamiton               5.00                                                 Tackifier (hydrogenated rosin ester)                                                                   15.00                                                (Trade name: Foral 105)                                                       Estradiol                0.50                                                 Medroxyprogesterone acetate                                                                            2.50                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 21

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               34.50                                                (Trade name: Califlex TR-1111)                                                Liquid paraffin          34.00                                                Polyisobutylene          8.00                                                 Crotamiton               3.00                                                 Super absorbent polymer  3.00                                                 (Trade name: Arasorb 800F)                                                    Tackifier (terpene hydrogenated resin)                                                                 15.00                                                (Trade name: Clearon P-105)                                                   Estradiol                0.50                                                 Medroxyprogesterone acetate                                                                            2.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of anestradiol/medroxyprogesterone acetate mixture type.

Example 22

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                               25.00                                                (Trade name: Califlex TR-1111)                                                Liquid paraffin          40.00                                                Crotamiton               4.00                                                 Tackifier (hydrogenated alicyclic hydrocarbon                                                          25.00                                                resin)                                                                        (Trade name: Escorez 5300)                                                    Estradiol                1.00                                                 Progesterone             5.00                                                 ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/progesteronemixture type.

Example 23

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             22.50                                                  (Trade name: Califlex TR-1107)                                                Polyisobutylene        5.00                                                   Liquid paraffin        36.50                                                  Crotamiton             5.00                                                   Super absorbent polymer                                                                              3.00                                                   (Trade name: Arasorb S-100F)                                                  Tackifier (rosin ester)                                                                              25.00                                                  (Trade name: KE-311)                                                          Estradiol              0.50                                                   Norethisterone acetate 2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 24

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             34.50                                                  (Trade name: Califlex TR-1111)                                                Liquid paraffin        40.50                                                  Crotamiton             3.00                                                   Super absorbent polymer                                                                              3.00                                                   (Trade name: Arasorb S-100F)                                                  Tackifier (rosin ester)                                                                              15.00                                                  (Trade name: KE-311)                                                          Estradiol              1.00                                                   Norethisterone acetate 3.00                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Example 25

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             25.00                                                  (Trade name: Califlex TR-1107)                                                Polyisobutylene        5.00                                                   Liquid paraffin        41.90                                                  Tackifier (rosin ester)                                                                              25.00                                                  (Trade name: KE-311)                                                          Crotamiton             0.10                                                   Estradiol              0.50                                                   Norethisterone acetate 2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Comparative Example 1

    ______________________________________                                        Styrene-isoprene-styrene block copolymer                                                             25.00                                                  (Trade name: Califlex TR-1107)                                                Polyisobutylene        5.00                                                   Liquid paraffin        42.00                                                  Tackifier (rosin ester)                                                                              25.00                                                  (Trade name: KE-311)                                                          Estradiol              0.50                                                   Norethisterone acetate 2.50                                                   ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of an estradiol/norethisteroneacetate mixture type.

Reference Example 1

    ______________________________________                                        Acryl resin-based solvent-type pressure sensitive                                                       92.00                                               adhesive                  (solid content)                                     (Trade name: NISSETSU PE-300, solid content 40%)                              Crotamiton                5.00                                                Estradiol                 0.50                                                Norethisterone acetate    2.50                                                ______________________________________                                    

The procedure of Example 1 was followed except that the aboveingredients were mixed together to form a mixture which was applied to abacking material (such as a support or liner) in such a manner that thethickness of the thus applied mixture on the backing material was thesame as those in the Examples after the solvent of the former has beenevaporated. The dried mixture attached to the backing material was cutinto pieces of a desired size to prepare a patch containing apercutaneously absorbable preparation of a estradiol/norethisteroneacetate mixture type.

Reference Example 2

    ______________________________________                                        Silicon adhesive        92.00                                                 (Trade name: Silascon 355 Medical Adhesive,                                                           (solid content)                                       solid content 18.5%)                                                          Crotamiton              5.00                                                  Estradiol               0.50                                                  Norethisterone acetate  2.50                                                  ______________________________________                                    

The procedure of Reference Example 1 was followed except that the aboveingredients were used, thereby to produce a patch containing apercutaneously absorbable preparation of a estradiol/norethisteroneacetate mixture type.

Experiment 1

(Percutaneous permeation test 1 on hairless mice)

Percutaneous permeation tests were made on hairless mice using thepatches obtained in Example 2 and Reference Examples 1-2, respectively.The results are shown in FIGS. 1 and 2. As is seen from the result, thepatch of Example 2 clearly exhibits excellent release of estradiol andnorethisterone acetate as compared with those of Reference Examples 1-2.This is because the preparation of the present invention contains the(A-B) n-A based elastomer, crotamiton and the softening agent as thebase component.

Experiment 2

(Percutaneous permeation test 2 on hairless mice)

Using each of the patches of Examples 15, 17 and 23 as well as the patchof Comparative Example 1, a percutaneous permeation test was made onhairless mice with the results being shown in FIGS. 3 and 4.

As is shown in the result, the patches of Examples 15, 17 and 23 clearlyindicate excellent release of estradiol as compared with that ofComparative Example 1. This is because the preparation of the presentinvention contains crotamiton.

Experiment 3

(Test for measuring the concentration of the medicinal ingredient in theblood of rabbits)

Using each of the patches of Examples 15, 17 and 23 as well as thepatches of Comparative Example 1, measurements for concentration of theactive ingredient in the blood of rabbits were made. Nipponwhite-colored hares were depilated at their back and then theconcentrations of estradiol and norethisterone acetate were measuredwith the lapse of time with the results being shown in FIGS. 5 and 6.

As is indicated in the results, the preparations of Examples 15, 17 and23 are excellent in the rise of concentration of the medicinalingredients in blood, the amount of the ingredients released anddurability as compared with that of Comparative Example 1.

Utilizability in the Industrial Field!

As mentioned above, the percutaneously absorbable preparation-containingpatch of this invention comprising as essential ingredients the (A-B)n-A based elastomer, crotamiton and the softening agent as well as twohormones, especially an estrogen exemplified by the estradiol and aluteal hormone, as an medicinal ingredient are most suitable for releaseof the medicinal ingredient therefrom, exhibit sufficient medicinalefficacy without causing rubefaction, rashes and the like when used.

We claim:
 1. A percutaneously absorbable preparation-containing patch, wherein the preparation comprises:(1) 20 to 99% by weight of a base comprising as essential ingredients:(a) 5 to 50% by weight of a (A-B)_(n) -A based elastomer, wherein A is substantially a monovinyl-substituted aromatic compound polymer block, B is substantially a conjugated diolefin copolymer block, and n is an integer of 3-7, (b) 1 to 20% by weight of crotamiton, and (c) 10 to 70% by weight of a softening agent; and (2) 0.01 to 10% by weight of estrogen and 0.01 to 10% by weight of a luteal hormone as active ingredients, the proportion of each ingredient being based on the total amount of the pharmaceutical preparation.
 2. A patch according to claim 1, wherein the preparation further contains 5 to 40% by weight of a tackifier.
 3. A patch according to claim 1, wherein the preparation further contains at most 15% by weight of a super absorbent polymer.
 4. A patch according to claim 1, 2 or 3, wherein the weight ratio of the content of the luteal hormone to the content of the estrogen is 1 to
 5. 5. A patch according to claim 1, 2, 3 or 4, wherein the estrogen is estradiol, estrone, equilin, equilenin or a derivative thereof.
 6. A patch according to claim 1, 2, 3 or 4, wherein the luteal hormone is progesterone, hydroxy-progesterone caproate, medroxyprogesterone acetate, dydrogesterone, chlormadinone acetate, ethisterone, dimethisterone, norethisterone, norethisterone acetate, norethisterone enanthate, ethynodiol acetate, megestrol acetate or allylestrenol.
 7. A patch according to claim 1, 2, 3, 4, 5 or 6, wherein the preparation is in a dosage form of a plaster. 